Ghrelin Acylation—A Post-Translational Tuning Mechanism Regulating Adult Hippocampal Neurogenesis

Abstract

Adult hippocampal neurogenesis—the generation of new functional neurones in the adult brain—is impaired in aging and many neurodegenerative disorders. We recently showed that the acylated version of the gut hormone ghrelin (acyl-ghrelin) stimulates adult hippocampal neurogenesis while the unacylated form of ghrelin inhibits it, thus demonstrating a previously unknown function of unacyl-ghrelin in modulating hippocampal plasticity. Analysis of plasma samples from Parkinson’s disease patients with dementia demonstrated a reduced acyl-ghrelin:unacyl-ghrelin ratio compared to both healthy controls and cognitively intact Parkinson’s disease patients. These data, from mouse and human studies, suggest that restoring acyl-ghrelin signalling may promote the activation of pathways to support memory function. In this short review, we discuss the evidence for ghrelin’s role in regulating adult hippocampal neurogenesis and the enzymes involved in ghrelin acylation and de-acylation as targets to treat mood-related disorders and dementia.

Ghrelin as a Biomarker of “Immunometabolic Depression” and Its Connection with Dysbiosis

“…The enzyme that catalyzes the octanoylation of ghrelin is ghrelin O-acyltransferase (GOAT), a member of the family membrane-bound O-acyl transferase (MBOAT). Octanoylation is achieved by attaching an eight-carbon medium-chain fatty acid (MCFA) (octanoate) to serine 3 of ghrelin [ 4 , 5 ] ( Figure 1 ). Ghrelin is the only peptide hormone in mammals that is acylated, which is crucial for its binding to GHS-R1a [ 6 ].…”

“…In depressed patients, these inverse correlations are also seen. Faecalibacterium [ 3 ] and Prevotellaceae [ 4 ] levels are reduced in patients with depression. Changes in the Bacteroidetes/Firmicutes ratio may also promote depression [ 5 ].…”

The 5:2 diet does not increase adult hippocampal neurogenesis or enhance spatial memory in mice

“…The precise mechanisms by which acyl‐ghrelin signalling mediates AHN remain unclear; however, this may be via non‐cell autonomous pathways involving the release of pro‐neurogenic factors (Buntwal et al , 2019; Sassi et al , 2022). More recently, we showed that acyl‐ghrelin increased BDNF mRNA—a neurotrophic factor—within the granule cell layer of the hippocampus (Hornsby et al , 2020).…”